The overall goal of this work is to target heparan sulfate as a novel therapeutic approach for myeloma. Although heparan sulfate is generally thought to inhibit tumor progression, recent discoveries by our lab and others point to a more sinister role for heparan sulfate proteoglycans---one of actually promoting growth of cancer. High levels of syndecan-1 shed by myeloma cells into the sera of patients is an indicator of poor prognosis, and we have discovered that soluble syndecan-1 promotes growth and metastasis of myeloma tumors in vivo. Because shed syndecan-1 accumulates within the marrow stromal matrix and in marrow plasma, it is strategically placed to facilitate the activities of many of the heparan sulfate-binding growth factors that drive myeloma progression (e.g., HGF, VEGF). Thus, heparan sulfate represents a unique target for myeloma therapy. We hypothesize that interfering with heparan sulfate function or availability within the bone marrow microenvironment will inhibit myeloma growth and dissemination. While therapeutic agents that target a single signaling pathway may work in some cancers, this will not likely be the case in myeloma where there exists extensive genetic and molecular heterogeneity. By blocking the normal function of heparan sulfate, there is an exciting opportunity to interfere with multiple signaling pathways that drive myeloma progression. Using murine models of myeloma, in Aim 1 we will determine if modifying or neutralizing heparan sulfate function, or inhibiting normal heparan sulfate expression will inhibit myeloma growth and dissemination. Our strategies for targeting heparan sulfate in vivo include i) modifying heparan sulfate function with enzymes; ii) neutralizing heparan sulfate with inhibitors of heparan sulfate function; and iii) inhibiting synthesis or expression of proteoglycans or heparan sulfate, or inhibiting shedding of syndecan-1 from the cell surface. In aim 2, new techniques in mass spectrometry will be employed to define the structure and ligand-binding capabilities of syndecan-1 heparan sulfate isolated from individual patients. Results will be mined for relatedness to other disease parameters (e.g., prognosis, response to treatment) and structural information used for design of new therapies that target specific heparan sulfate-mediated signaling pathways. Together, these studies will determine the potential of heparan sulfate-based therapeutics for myeloma.